title: ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death.
abstract: Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy-induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy-induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT-treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants.
authors.affiliation: Cell Death Research and Therapy Unit; Department of Cellular and Molecular Medicine; University of Leuven (KU Leuven); Leuven, Belgium.
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Dudek
authors.forename: Gabriela B
authors.initials: GB
authors.lastname: Ferreira
authors.forename: Tom
authors.initials: T
authors.lastname: Verfaillie
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Krysko
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000873:Anthracenes; D001343:Autophagy / Q000187:drug effects* / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D037282:Calreticulin / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005979:Glutathione Peroxidase / Q000378:metabolism; D006639:Histidine / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D010778:Photochemotherapy; D017382:Reactive Oxygen Species / Q000494:pharmacology*
chemical_list: C502778:ATG5 protein, human; D000873:Anthracenes; D000071187:Autophagy-Related Protein 5; D037282:Calreticulin; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D006639:Histidine; D010569:Perylene; C004965:hypericin; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D005979:Glutathione Peroxidase
keywords: ATP; T cells; autophagy; calreticulin; cancer; dendritic cells; immunogenic cell death; photodynamic therapy (PDT)